The overarching objective of the Massachusetts Alzheimer's Disease Research Center (MADRC) is to stimulate and support research of the highest quality in aging, Alzheimer's disease (AD), and related disorders. The specific goals are: To propose and support new research directed toward uncovering the etiology and pathogenetic mechanisms of AD and related dementias;to enhance collaborative research funded outside of the MADRC;and to catalyze education, training and information transfer related to dementia. Administrative, Clinical, Data and Statistical, Neuropathology, and Education Cores support 3 R01 style 5 year projects and 3 pilot projects/year. The Clinical Core has established a Longitudinal Cohort that follows ~600 individuals who are cognitively normal, have mild impairments, mild AD or other dementias. These subjects undergo full Uniform Data Set evaluations and data are submitted to NACC. Our retention rate to date (93% 1 year;97% 2 year) shows that these individuals are committed to participate in longitudinal studies. Over 60% of these individuals have already also contributed to at least one other research project related to aging and cognition, including 7 different neuroimaging studies and a major Biomarkers program. The Neuropathology Core has tissues on nearly 1400 subjects, and in the last 4 years supplied 3 dozen separate investigators with over 10,000 slides or specimens. The Data and Statistics Core has built a new state of the art data repository. The Education Core has continued its mission of outstanding community involvement, and has enhanced recruitment for MADRC programs. Three R01 style applications are closely linked to Core activities, and focus on the relationship between amyloid, clinical symptoms, and neurotoxicity: Two relate to longitudinal studies in MADRC subjects. The first asks what does positive PIB amyloid imaging mean in the setting of normal cognition? The second, led by a junior investigator, examines whether amyloid deposition in vessels (CAA) alters the course of dementia. The third project utilizes MADRC brain bank material to examine whether oligomeric forms of amyloid - in addition to, or instead of, fibrillar forms - are neurotoxic. The MADRC provides infrastructure to support local and national efforts in AD research: In the current grant period 44 investigators used MADRC resources to support 76 NIH funded projects;an additional 68 projects supported by non-Federal sources relied in part on MADRC for subjects or other resources. Going forward, the MADRC will continue to expand its clinical and neuropathological resources, its innovative training and scientific programs directed toward AD research.